In 1989, a main causative virus of non-A non-B post-transfusion hepatitis was found and named hepatitis C virus (HCV). Since then, several types of hepatitis viruses have been found besides type A, type B and type C, wherein hepatitis caused by HCV is called hepatitis C. The patients infected with HCV are considered to involve several percent of the world population, and the infection with HCV characteristically becomes chronic.
HCV is an envelope RNA virus, wherein the genome is a single strand plus-strand RNA, and belongs to the genus Hepacivirus of Flavivirus (from The International Committee on Taxonomy of Viruses, International Union of Microbiological Societies). Of the same hepatitis viruses, for example, hepatitis B virus (HBV), which is a DNA virus, is eliminated by the immune system and the infection with this virus ends in an acute infection except for neonates and infants having yet immature immunological competence. In contrast, HCV somehow avoids the immune system of the host due to an unknown mechanism. Once infected with this virus, even an adult having a mature immune system frequently develops persistent infection.
When chronic hepatitis is associated with the persistent infection with HCV, it advances to cirrhosis or hepatic cancer in a high rate. Enucleation of tumor by operation does not help much, because the patient often develops recurrent hepatic cancer due to the sequela inflammation in non-cancerous parts.
Thus, an effective therapeutic method of treating or controlling hepatitis C is desired. Apart from the symptomatic therapy to suppress inflammation with an anti-inflammatory agent, the development of a therapeutic agent that reduces HCV to a low level free from inflammation and that eradicates HCV has been strongly demanded. An optimal therapeutic agent would provide a virologic response classified as a “sustained virologic response,” which is defined as undetectable levels of virus in blood six months or more after completing hepatitis C therapy.
At present, a treatment with interferon, as a single agent or in combination with ribavirin, is the only effective method known for the eradication of HCV. However, interferon can eradicate the virus in only about one-third of the patient population. For the rest of the patients, it has no effect or provides only a temporary effect. Therefore, an anti-HCV drug to be used in the place of or concurrently with interferon is awaited in great expectation.
Cyclosporine A is well known for its immunosuppressive activity and a range of therapeutic uses, including antifungal, anti-parasitic, and anti-inflammatory as well as anti-HIV activity. Cyclosporine A and certain derivatives have been reported as having anti-HCV activity, see Watashi et al., Hepatology, 2003, Volume 38, pp 1282-1288, Nakagawa et al., Biochem. Biophys. Res. Commun. 2004, Volume 313, pp 42-7, and Shimotohno and K. Watashi, 2004 American Transplant Congress, Abstract No. 648 (American Journal of Transplantation 2004, Volume 4, Issue s8, Pages 1-653). Cyclosporine derivatives having HCV activity are known from International Publication Nos. WO2005/021028, WO2006/039668 and WO2006/038088.
Cyclosporines substituted in the 8-position by a group other than (D)-Alanine are known from EP0056782, EP0414632, EP 0444897, U.S. Pat. Nos. 4,639,434 and 5,214,130, PCT publication No. WO2004/072108. These compounds are described as having immunosuppressive and/or anti-inflammatory properties. Schote et al, Journal of Pharmaceutical Sciences, March 2002, Volume 91, No. 3 pages 856-867 describes a cyclosporine in which the D-Alanine at the 8-position is replaced by the hydrochloride salt of D-2,3 diaminopropionic acid. Cruz et al, Antimicrobial agents and Chemotherapy, January 2000, Volume 44, No. 1, pages 143-149 describes a cyclosporine in which the D-Alanine in the 8-position is substituted by acetylamino having activity against fluconozole-sensitive and resistant Cryptoccus neoformans isolates (a fungal pathogen). Ko et al, Helvetica Chimica Acta, 1997, Volume 80, No. 3, pages 695-705 describes immunosuppressive cyclosporines in which the D-Alanine in the 8-position is replaced by D-Asparagine and D-Glutamine. Sigal et al, The Journal of Experimental Medicine, 1991, Volume 173, pages 619-628 describes a cyclosporin analogue substituted in the 8-position. D-alanine at the 8-position was replaced by both D-2,3-diaminopropionic acid and D-2,4-diaminobutyric acid in Journal of Immunology, 1993, Volume 50, page 2139 (although it appears that these were named incorrectly in this paper as D-1,3-diaminopropionic acid and D-1,4-diaminobutyric acid, respectively. Immunosuppressive activity was reported in this paper.
Colucci et al, J. Org. Chem., 1990, Volume 55, page 2985-2903 describes the synthesis of [D-lysyl]8cyclosporine, which is also described by Loor et al in J. Med, Chem. 2002, Volume 45, pages 4598-4612 and pages 4613-4628 and by Billich et al, Journal of Virology, 1995, Volume 69, No. 4, pages 2451-2461. In particular, Billich et al states that [D-lysyl]8cyclosporine does not inhibit antiviral activity when tested against HIV-1. Surprisingly it has been found that [D-lysyl]8cyclosporine does have antiviral activity against HCV.
In one aspect the present invention seeks to provide cyclosporine derivatives having activity against HCV.
In a further aspect the present invention seeks to provide novel cyclosporine derivatives having activity against HCV with an improved safety margin (i.e. the difference between the dose level of compound required to provide effective control of HCV and the dose levels producing toxicity).
In a further aspect the present invention seeks to provide cyclosporine derivatives having activity against both HCV and HIV.